This study investigates effects of beta-adrenergic blockade on total silent ischemic time assessed by ambulatory electrocardiographic monitoring and its relation to heart rate and time of day in ambulatory men with coronary artery disease. Metoprolol, when titrated to optimal dose in a controlled trial in 9 patients, reduced both total silent ischemic time (from 156 +/- 65 to 20 +/- 15 minutes, p = 0.04) and frequency of silent ischemic episodes (from 8 +/- 2 to 2 +/- 2 episodes, p = 0.03) compared with placebo. Mean daily heart rate was reduced, from 82 +/- 2 beats/min during placebo to 58 +/- 1 beats/min, as was heart rate at onset of 1 mm of ST-segment depression (106 +/- 2 to 74 +/- 4 beats/min, both p less than 0.001). Heart rate increased 10 +/- 1 beats/min during silent ischemia with placebo therapy, but increased only 4 +/- 1 beats/min during metoprolol treatment (p less than 0.03). During placebo administration the largest proportion of silent ischemic time occurred between 0600 and 1200 hours. Metoprolol attenuated this circadian variation in silent ischemia while reducing (p less than 0.05) total silent ischemic time in all periods. Thus, beta-adrenergic blockade reduces the frequency of silent myocardial ischemic episodes and total silent ischemic time, while mean daily heart rate and heart rate at onset of ischemia and maximal ischemia decrease. Metoprolol treatment also attenuates circadian variation of silent ischemia. These data may be interpreted to suggest that beta-adrenergic activation operates in the pathogenesis of silent myocardial ischemia and its circadian variation.